Abstract

Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects - the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man.

Data availability

Figure 5 - Source Data 1, Figure 6 - Source Data 1 and Figure 7 - Source Data 1 contain the numerical data used to generate the figures.

Article and author information

Author details

  1. Guillaume Martinez

    CHU Grenoble-Alpes, Grenoble, France
    For correspondence
    gmartinez@chu-grenoble.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7572-9096
  2. Charles Coutton

    CHU Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Corinne Loeuillet

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Caroline Cazin

    CHU Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Jana Muroňová

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Magalie Boguenet

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Emeline Lambert

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Magali Dhellemmes

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Geneviève Chevalier

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Jean-Pascal Hograindleur

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Charline Vilpreux

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Yasmine Neirijnck

    Department of Genetic Medicine and Development, University of Geneva Medical School, Genève, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  13. Zine Eddine Kherraf

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Jessica Escoffier

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8166-5845
  15. Serge Nef

    Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  16. Pierre F Ray

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    Competing interests
    The authors declare that no competing interests exist.
  17. Christophe Arnoult

    Institute for Advanced Biosciences, INSERM, CNRS, University Grenoble-Alpes, Grenoble, France
    For correspondence
    christophe.arnoult@univ-grenoble-alpes.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3753-5901

Funding

Agence Nationale de la Recherche (ANR-19-CE17-0014)

  • Pierre F Ray
  • Christophe Arnoult

Agence Nationale de la Recherche (ANR-21-CE17-0007)

  • Guillaume Martinez
  • Charles Coutton

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were conducted according to a protocol approved by the local Ethics Committee (ComEth Grenoble No. 318), by the French government (ministry agreement number #7128 UHTA-U1209-CA), and by the Direction Générale de la Santé (DGS) for the State of Geneva.

Copyright

© 2022, Martinez et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Guillaume Martinez
  2. Charles Coutton
  3. Corinne Loeuillet
  4. Caroline Cazin
  5. Jana Muroňová
  6. Magalie Boguenet
  7. Emeline Lambert
  8. Magali Dhellemmes
  9. Geneviève Chevalier
  10. Jean-Pascal Hograindleur
  11. Charline Vilpreux
  12. Yasmine Neirijnck
  13. Zine Eddine Kherraf
  14. Jessica Escoffier
  15. Serge Nef
  16. Pierre F Ray
  17. Christophe Arnoult
(2022)
Oligogenic heterozygous inheritance of sperm abnormalities in mouse
eLife 11:e75373.
https://doi.org/10.7554/eLife.75373

Share this article

https://doi.org/10.7554/eLife.75373

Further reading

    1. Cell Biology
    2. Evolutionary Biology
    Paul Richard J Yulo, Nicolas Desprat ... Heather L Hendrickson
    Research Article

    Maintenance of rod-shape in bacterial cells depends on the actin-like protein MreB. Deletion of mreB from Pseudomonas fluorescens SBW25 results in viable spherical cells of variable volume and reduced fitness. Using a combination of time-resolved microscopy and biochemical assay of peptidoglycan synthesis, we show that reduced fitness is a consequence of perturbed cell size homeostasis that arises primarily from differential growth of daughter cells. A 1000-generation selection experiment resulted in rapid restoration of fitness with derived cells retaining spherical shape. Mutations in the peptidoglycan synthesis protein Pbp1A were identified as the main route for evolutionary rescue with genetic reconstructions demonstrating causality. Compensatory pbp1A mutations that targeted transpeptidase activity enhanced homogeneity of cell wall synthesis on lateral surfaces and restored cell size homeostasis. Mechanistic explanations require enhanced understanding of why deletion of mreB causes heterogeneity in cell wall synthesis. We conclude by presenting two testable hypotheses, one of which posits that heterogeneity stems from non-functional cell wall synthesis machinery, while the second posits that the machinery is functional, albeit stalled. Overall, our data provide support for the second hypothesis and draw attention to the importance of balance between transpeptidase and glycosyltransferase functions of peptidoglycan building enzymes for cell shape determination.

    1. Cell Biology
    2. Developmental Biology
    Pavan K Nayak, Arul Subramanian, Thomas F Schilling
    Research Article

    Mechanical forces play a critical role in tendon development and function, influencing cell behavior through mechanotransduction signaling pathways and subsequent extracellular matrix (ECM) remodeling. Here we investigate the molecular mechanisms by which tenocytes in developing zebrafish embryos respond to muscle contraction forces during the onset of swimming and cranial muscle activity. Using genome-wide bulk RNA sequencing of FAC-sorted tenocytes we identify novel tenocyte markers and genes involved in tendon mechanotransduction. Embryonic tendons show dramatic changes in expression of matrix remodeling associated 5b (mxra5b), matrilin1 (matn1), and the transcription factor kruppel-like factor 2a (klf2a), as muscles start to contract. Using embryos paralyzed either by loss of muscle contractility or neuromuscular stimulation we confirm that muscle contractile forces influence the spatial and temporal expression patterns of all three genes. Quantification of these gene expression changes across tenocytes at multiple tendon entheses and myotendinous junctions reveals that their responses depend on force intensity, duration and tissue stiffness. These force-dependent feedback mechanisms in tendons, particularly in the ECM, have important implications for improved treatments of tendon injuries and atrophy.